3.4　Repeated Caerulein Models

The secretagogue hyperstimulation model is by far the most frequently used technique for induction of acute pancreatitis.This method was first used by Lampel and Kern who intravenously applied caerulein，an ortholog of the intestinal hormone cholecystokinin，to rats and observed signs of acute interstitial pancreatitis（Lampel and Kern 1977）.Pancreatitis usually resolves spontaneously.This model was broadly adopted and modified to secretagogue application given intraperitoneally which is as effective but less technically challenging.Usually the required dose exceeds tenfold the concentration needed for maximal physiological secretion from the exocrine pancreas.Later caerulein-injection models were modified again to establish experimental chronic pancreatitis following the idea that multiple bouts of acute pancreatitis finally lead to chronic disease（Lerch and Gorelick 2013）.Normally pro-fibrogenic cytokines peak within 3 or 4 days after acute pancreatitis and normalize within 1 week but reinjury before normalization of the profibrogenic milieu favors chronic pancreatic injury.TGF-beta is believed to regulate extracellular matrix deposition as it is elevated during the vulnerable phase of acute pancreatitis and，when inhibited，collagen and fibronectin production are reduced（Gress et al.1994；Menke et al.1997）.Increase of TGF-beta was not only observed in caerulein-induced acute pancreatitis but also in an obstruction model（duodenal loop closure）underlining its general importance during acute pancreatitis（Kimura et al.1995）.

Supraphysiologic concentrations of caerulein given two or three times a week for up to 6-10 weeks showed substantial pancreatic fibrosis in line with a strong increase of procollagen I expression（Neuschwander-Tetri et al.2000a，b）.Longer intervals of caerulein applications seemed to be no more effective.No or hardly any fibrosis was observed during weekly applications unless recombinant TGF-beta was given additionally（Van Laethem et al.1996）.When intervals were extended up to 20 days no sustainable signs of fibrosis were seen（Elsasser et al.1992）.(https://www.daowen.com)

Although chronic fibrotic changes can be generated successfully by repeated caerulein applications it remains unclear whether exocrine or endocrine insufficiency can be achieved.Diabetes was observed in an experimental model in rats using caerulein injections plus water-immersion stress（Goto et al.1995；Miyahara et al.1999）.Stress or caerulein alone did not cause endocrine insufficiency.The intrapancreatic protein content，reflecting exocrine function，was nearly halved when mice were treated with caerulein（three times a week）and lipolysaccharide for 6 weeks（Ohashi et al.2006）.

There are several other noxious agents that have been combined with caerulein hyperstimulation to induce experimental chronic pancreatitis.Some of them will be introduced in the following sections.